Project 3 Each year up to 500,000 individuals survive hospitalization with severe sepsis, but within five years half of them will be dead. Early clinical and experimental evidence indicates that a non-resolving inflammatory response persists long after the discharge from hospital, and contributes to cognitive dysfunction, impaired immune responses, and poor quality of life. The hypothesis addressed in this project is that cytokines produced in the periphery activate production of cytokines in the brain. These mediate behavioral and immunological sequelae in sepsis survivors. Based on our previous work, the data available in the published literature, and our preliminary studies we will address this hypothesis through the following specific ainis. Aim 1: Determine effects of therapeutically targeting brain cytokine release in sepsis survivors. Aim 2: Determine effects of therapeutically targeting systemic cytokine release in sepsis survivors. Aim 3: To study the inflammatory reflex in sepsis survivors. The anticipated results will provide mechanistic insights and potentially identify therapeutic strategies. RELEVANCE (See instructions): Recent evidence indicates that sepsis survivors experience cognitive and immune impairment, and more than half of the survivors die within 5 years. The studies proposed here will provide significant data that can be used to modulate neural and immune function to develop therapeutic modalities for the prevention and treatment of sepsis induced cognitive and immune impairments.